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Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory\/relapsed cHL in contrast with responders. Therefore, ultra-deep next-generation panel-sequencing was performed on a total of 59 FFPE-samples (20 responders, 26 relapsed (rHL: 11 initial-diagnosis, 15 relapse) and 13 primary-refractory (prHL: 8 initial-diagnosis, 5 progression) from 44 cHL-patients applying a hybrid-capture approach. We compared samples associated with distinct disease courses concerning their oncogenic drivers, mutational signatures, and perturbed pathways. Compared to responders, mutations in genes such as <jats:italic>PMS2, PDGFRB, KAT6A, EPHB1,<\/jats:italic> and <jats:italic>HGF<\/jats:italic> were detected more frequently in prHL\/rHL. Additionally, we observed that in rHL or prHL, <jats:italic>BARD1-<\/jats:italic>mutations occur, whereas <jats:italic>ETV1, NF1,<\/jats:italic> and <jats:italic>MET<\/jats:italic>-mutations were eliminated through clonal selection. A significant enrichment of non-synonymous variants was detected in prHL compared to responders and a significant selection process in favor of NOTCH-pathway mutations driving rHL or prHL was observed. However, our analysis revealed a negative selection process for non-synonymous variants affecting the hippo-pathway. This study delineates distinct mutational signatures between responders and rHL\/prHL, whilst illustrating longitudinal dynamics in mutational profiles using paired samples. Further, several exploitable therapeutic vulnerabilities for rHL and prHL were identified.<\/jats:p>","DOI":"10.1007\/s00277-025-06274-5","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T15:09:32Z","timestamp":1740409772000},"page":"1721-1733","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The mutational landscape and its longitudinal dynamics in relapsed and refractory classic Hodgkin lymphoma"],"prefix":"10.1007","volume":"104","author":[{"given":"Hanno","family":"Witte","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axel","family":"K\u00fcnstner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Bernard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"St\u00f6lting","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Kusch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumar","family":"Nagarathinam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cyrus","family":"Khandanpour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolas","family":"von Bubnoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Grunert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svenja","family":"Hartung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annette","family":"Arndt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konrad","family":"Steinestel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hartmut","family":"Merz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hauke","family":"Busch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfred C.","family":"Feller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niklas","family":"Gebauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,24]]},"reference":[{"issue":"10114","key":"6274_CR1","doi-asserted-by":"publisher","first-page":"2790","DOI":"10.1016\/S0140-6736(17)32134-7","volume":"390","author":"P Borchmann","year":"2017","unstructured":"Borchmann P, Goergen H, Kobe C et al (2017) PET-guided treatment in patients with advanced-stage Hodgkin\u2019s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. 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